compound 8e [PMID: 24432909]   Click here for help

GtoPdb Ligand ID: 8137

Compound class: Synthetic organic
Comment: Compound 8e it was tested in a medicinal chemistry study to identify small molecule inhibitors of mutated anaplastic lymphoma kinase (Alk) which confer crizotinib resistance [1].
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2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 7
Hydrogen bond donors 3
Rotatable bonds 7
Topological polar surface area 159.92
Molecular weight 470.15
XLogP 2.51
No. Lipinski's rules broken 0
SMILES / InChI / InChIKey
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Canonical SMILES OCC(c1nc(c(s1)c1cnc(c(c1)OC(c1cc(F)ccc1n1nccn1)C)N)C)(O)C
Isomeric SMILES OC[C@](c1nc(c(s1)c1cnc(c(c1)O[C@@H](c1cc(F)ccc1n1nccn1)C)N)C)(O)C
InChI InChI=1S/C22H23FN6O3S/c1-12-19(33-21(28-12)22(3,31)11-30)14-8-18(20(24)25-10-14)32-13(2)16-9-15(23)4-5-17(16)29-26-6-7-27-29/h4-10,13,30-31H,11H2,1-3H3,(H2,24,25)/t13-,22-/m1/s1
InChI Key DIXMBHMNEHPFCX-MCMMXHMISA-N
Bioactivity Comments
Compound 8e effectively inhibits Alk phosphorylation in engineered cells lines expressing wild type and mutant Alk [1]. Compound 8e also inhibits kinase activity of ROS1, FER, LTK, TrkB, FES (IC50s all < 10nM) and several other kinases at IC50 values >10nM [1].
Selectivity at enzymes
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Target Sp. Type Action Value Parameter Concentration range (M) Reference
FER tyrosine kinase Hs Inhibitor Inhibition 8.7 pIC50 - 1
pIC50 8.7 (IC50 2x10-9 M) [1]
FES proto-oncogene, tyrosine kinase Hs Inhibitor Inhibition 8.3 pIC50 - 1
pIC50 8.3 (IC50 5x10-9 M) [1]
mitogen-activated protein kinase kinase kinase 9 Hs Inhibitor Inhibition 7.4 pIC50 - 2
pIC50 7.4 (IC50 3.8x10-8 M) [2]
Selectivity at catalytic receptors
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Target Sp. Type Action Value Parameter Concentration range (M) Reference
c-ros oncogene 1, receptor tyrosine kinase Hs Inhibitor Inhibition 10.7 pKi - 1
pKi 10.7 (Ki 2x10-11 M) [1]
Description: Value calculated from tight-binding (Morrison) equation for competitive inhibitors tested in a Pfizer mobility shift assay.
ALK receptor tyrosine kinase Primary target of this compound Hs Inhibitor Inhibition 9.1 pIC50 - 1
pIC50 9.1 (IC50 8x10-10 M) [1]
leukocyte receptor tyrosine kinase Hs Inhibitor Inhibition 8.7 pIC50 - 1
pIC50 8.7 (IC50 2x10-9 M) [1]
neurotrophic receptor tyrosine kinase 2 Hs Inhibitor Inhibition 8.4 pIC50 - 1
pIC50 8.4 (IC50 4x10-9 M) [1]